This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.
NOTE: This memo was distributed with Blue Book Memorandum #G95-1,
entitled Use of International Standard ISO-10993, "Biological
Evaluation of Medical Devices Part 1: Evaluation and Testing" and
relates to implementation of #G95-1.
May 1, 1995
Director, Office of Device Evaluation (ODE)
Required Biocompatibility Training and Toxicology Profiles for
Evaluation of Medical Devices
Division Directors, ODE
The new blue book memorandum #G95-1 entitled "Use of International
Standard ISO-10993, "Biological Evaluation of Medical Devices Part-1:
Evaluation and Testing," includes an FDA-modified matrix that
designates the type of testing needed for various medical devices
(copy attached). It also includes a flow chart entitled
"Biocompatibility Flow Chart for the Selection of Toxicity Tests for
510(k)s." The guidance will be effective for all submissions that
will be received on or after July 1, 1995. The former guidance, #G87-
1 entitled "Tripartite Biocompatibility Guidance," may continue to be
applied until a final decision is reached on each submission received
prior to July 1, 1995. Sponsors may, however, choose to follow this
new memorandum immediately. In addition, questions presented to staff
by submitters regarding this change in biocompatibility testing should
be discussed with you to determine the most appropriate resolution of
the issues.
To implement the new blue book policy, it is essential that we train
all our reviewers in the proper use of the ISO-10993 with modified
matrix. I have asked Dr. Raju Kammula to arrange training sessions to
train all reviewers in ODE.
Through CDRH Staff College he will be scheduling several training
sessions to discuss the differences between the Tripartite and ISO
guidances and how to use the new bluebook guidance with modified ISO
matrix. These training sessions will be conducted in May and June.
Please advise all reviewers in your division to attend a training
session so that they will be fully informed and knowledgeable on how
to use the ISO standard before July 1, 1995.
I have also asked Raju Kammula to coordinate the development of
toxicology profiles for devices in prolonged and permanent contact
categories and devices with a significantly large volume of
submissions. Each division must identify the appropriate devices and
develop these profiles. Please provide the name of at least one
individual to work with Raju Kammula to develop these profiles.
Attachment
cc: D. Bruce Burlington M.D.
General Program Memorandum - #G95-1
May 1, 1995
Director, Office of Device Evaluation (ODE)
Use of International Standard ISO-10993, "Biological Evaluation of
Medical Devices Part 1: Evaluation and Testing"
ODE Reviewing Staff
Purpose
The purpose of this memo is to replace, after July 1, 1995, the use of
ODE General Program Memorandum G87-1, entitled "Tripartite
Biocompatibility Guidance", dated April 24, 1987 with Part-1 of the ISO
standard "Biological Evaluation of Medical Devices", which includes an
FDA-modified matrix.
Background
Biological evaluation of medical devices is performed to determine the
potential toxicity resulting from contact of the component materials of
the device with the body. The device materials should not, either
directly or through the release of their material constituents:
(i) produce adverse local or systemic effects; (ii) be carcinogenic;
or, (iii) produce adverse reproductive and developmental effects.
Therefore, evaluation of any new device intended for human use requires
data from systematic testing to ensure that the benefits provided by
the final product will exceed any potential risks produced by device
materials.
When selecting the appropriate tests for biological evaluation of a
medical device, one must consider the chemical characteristics of
device materials and the nature, degree, frequency and duration of its
exposure to the body. In general, the tests include: acute, sub-
chronic and chronic toxicity; irritation to skin, eyes and mucosal
surfaces; sensitization; hemocompatibility; genotoxicity;
carcinogenicity; and, effects on reproduction including developmental
effects. However, depending on varying characteristics and intended
uses of devices as well as the nature of contact, these general tests
may not be sufficient to demonstrate the safety of some specialized
devices. Additional tests for specific target organ toxicity, such as
neurotoxicity and immunotoxicity may be necessary for some devices.
For example, a neurological device with direct contact with brain
parenchyma and cerebrospinal fluid (CSF) may require an animal implant
test to evaluate its effects on the brain parenchyma, susceptibility to
seizure, and effects on the functional mechanism of choroid plexus and
arachnoid villi to secrete and absorb (CSF). The specific clinical
application and the materials used in the manufacture of the new device
determines which tests are appropriate.
Some devices are made of materials that have been well characterized
chemically and physically in the published literature and have a long
history of safe use. For the purposes of demonstrating the substantial
equivalence of such devices to other marketed products, it may not be
necessary to conduct all the tests suggested in the FDA matrix of this
guidance. FDA reviewers are advised to use their scientific judgement
in determining which tests are required for the demonstration of
substantial equivalence under section 510(k). In such situations, the
manufacturer must document the use of a particular material in a
legally marketed predicate device or a legally marketed device with
comparable patient exposure.
International Guidance and Standards
In 1986, FDA, Health and Welfare Canada, and Health and Social Services
UK issued the Tripartite Biocompatibility Guidance for Medical Devices.
This Guidance has been used by FDA reviewers, as well as by
manufacturers of medical devices, in selecting appropriate tests to
evaluate the adverse biological responses to medical devices. Since
that time, the International Standards Organization (ISO), in an effort
to harmonize biocompatibility testing, developed a standard for
biological evaluation of medical devices (ISO 10993). The scope of
this 12-part standard is to evaluate the effects of medical device
materials on the body. The first part of this standard "Biological
Evaluation of Medical Devices: Part 1: Evaluation and Testing",
provides guidance for selecting the tests to evaluate the biological
response to medical devices. Most of the other parts of the ISO
standard deal with appropriate methods to conduct the biological tests
suggested in Part 1 of the standard.
ISO 10993, Part 1, and the FDA-modified Matrix
The ISO Standard, Part 1, uses an approach to test selection that is
very similar to the currently-used Tripartite Guidance, including the
same seven principles. It also uses a tabular format (matrix) for
laying out the test requirements based on the various factors discussed
above. The matrix consist of two tables. See Attachment A, Table 1 -
Initial Evaluation Tests for Consideration, and Attachment B, Table 2 -
Supplementary Evaluation Tests for Consideration. Attachment C is a
biocompatibility flow chart for the selection of toxicity tests for
510(k)s. It may be applicable to some PMAs also but not all PMAs. In
addition, FDA is in the process of preparing toxicology profiles for
specific devices. These profiles will assist in determining
appropriate toxicology tests for these devices.
To harmonize biological response testing with the requirements of other
countries, FDA will apply the ISO standard, Part 1, in the review
process in lieu of the Tripartite Biocompatibility Guidance.
FDA notes that the ISO standard acknowledges certain kinds of
discrepancies. It states "due to diversity of medical devices, it is
recognized that not all tests identified in a category will be
necessary and practical for any given device. It is indispensable for
testing that each device shall be considered on its own mertis:
additional tests not indicated in the table may be necessary." In
keeping with this inherent flexibility of the ISO standard, FDA has
made several modifications to the testing required by ISO 10993-Part 1.
These modifications are required for the category of surface devices
permanently contacting mucosal membranes (e.g., IUDs). The ISO
standard would not require acute, sub-chronic, chronic toxicity and
implantation tests. Also, for externally communicating devices,
tissue/bone/dentin with prolonged and permanent contact (e.g., dental
cements, filling materials etc.), the ISO standard does not require
irritation, systemic toxicity, acute, sub-chronic and chronic toxicity
tests. Therefore, FDA has included these types of tests in the matrix.
Although several tests were added to the matrix, reviewers should note
that some tests are commonly requested while other tests are to be
considered and only asked for on a case-by-case basis. Thus, the
modified matrix is only a framework for the selection of tests and not
a checklist of every required test. Reviewers should avoid
proscriptive interpretation of the matrix. If a reviewer is uncertain
about the applicability of a specific type of test for a specific
device, the reviewer should consult toxicologists in ODE.
FDA expects that manufacturers will consider performing the additional
tests for certain categories of devices suggested in the FDA-modified
matrix. This does not mean that all the tests suggested in the
modified matrix are essential and relevant for all devices. In
addition, device manufacturers are advised to consider tests to detect
chemical components of device materials which may be pyrogenic. We
believe that ISO 10993, Part 1, and appropriate consideration of the
additional tests suggested by knowledgeable individuals will generate
adequate biological data to meet FDA's requirements. Reviewers in the
Office of Device Evaluation will accept data developed according to the
ISO-10993, Part 1, with the matrix as modified and presented in this
memorandum (#G95-1).
Manufacturers are advised to initiate discussions with the appropriate
review division in the Office of Device Evaluation, CDRH, prior to the
initiation of expensive, long-term testing of any new device materials
to ensure that the proper testing will be conducted. We also recognize
that an ISO standard is a document that undergoes periodic review and
is subject to revision. ODE will notify manufacturers of any future
revisions to the ISO standard referenced here that affect this
document's requirements and expectations.
Effective Date: This Guidance is effective for all submissions that
will be received on or after July 1, 1995. The former guidance, G87-1
entitled "Tripartite Biocompatibility Guidance," may continue to be
applied until a final decision is reached on each submission received
prior to July 1, 1995. Sponsors may, however, choose to follow this
new memorandum immediately. After this transition period for
submissions covered by the Tripartite Biocompatibility Guidance, G87-1
will be recinded and replaced by this guidance.
Susan Alpert, Ph.D., M.D.
Attachment A
Attachment B
Attachment C
Updated May 9, 1996
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